Crosslinkable polymer compositions

ABSTRACT

The present disclosure pertains to crosslinkable compositions and systems as well as methods for forming crosslinked compositions in situ, including the use of the same for controlling the movement of bodily fluid within a patient, among many other uses.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/635,858, filed Oct. 17, 2019, which is a continuation of U.S.application Ser. No. 16/288,163, filed Feb. 28, 2019 and entitled“CROSSLINKABLE POLYMER COMPOSITIONS”, and which claims the benefit ofU.S. Provisional Application No. 62/809,254, filed Feb. 22, 2019 andentitled “CROSSLINKABLE POLYMER COMPOSITIONS”, each of which is herebyincorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosure pertains to crosslinkable compositions andsystems as well as methods for forming crosslinked compositions in situ,including the use of the same for controlling the movement of bodilyfluid within a patient, among many other uses.

BACKGROUND

Crosslinkable compositions that are capable of forming crosslinkedcompositions in situ, have a number of important biomedical applicationsincluding vascular embolization, treatment of arteriovenousmalformation, treatment of AV fistulas, treatment of abdominal aorticaneurysms, space filling and bulking (e.g. following surgical resection,or for cosmetic purposes), prevention of tissue adhesion, hernia repair,prevention or treatment of reflux, temporary or permanent occlusion ofbody lumens for a variety of applications including sterilization andprevention of calculus migration during lithotripsy, treatment ofhemorrhage, particularly from non-compressible or difficult-to-visualizewounds, and other applications.

The diversity of applications for in-situ-forming crosslinkedcompositions reflects significant advantages possessed by such implantsincluding, without limitation the ability to deliver in-situ-formingcrosslinked compositions to closed cavities, for exampleintravascularly, the ability to deliver in-situ-forming crosslinkedcompositions to difficult-to-access body sites, the ability ofin-situ-forming crosslinked compositions to fill empty space, potentialspace, or fill space filled with blood, support surrounding tissues, andso forth.

SUMMARY OF THE INVENTION

The present disclosure pertains to crosslinkable compositions andsystems as well as methods for forming crosslinked compositions in situ.

In some aspects, the present disclosure pertains to a compositioncomprising a first polysiloxane having two or more unsaturated groups(i.e., groups containing carbon-carbon double bonds and/or groupscontaining carbon-carbon triple bonds), a first silanol compound, afirst filler, a first hydride material having two or more hydridegroups, and a catalyst for catalyzing a reaction between the unsaturatedgroups and the hydride groups, in which (a) the composition may have aviscosity as measured by oscillatory rheology at 0.1 Hz and 1% strain at25° C. that is at least ten-fold, beneficially at leastone-hundred-fold, more beneficially at least five-hundred-fold, greaterthan a viscosity of the composition as measured by flow rheology at afrequency of 30 Hz at 25° C., (b) the composition may cure when measuredat 37° C., within a time period of 1 minute to 120 minutes, beneficially15 minutes to 120 minutes, (c) after being allowed to anneal for aperiod of 7 days at 70° C., the composition may have a viscosity asmeasured using oscillatory rheology at a frequency of 0.1 Hz and astrain of 1% at 25° C. or 37° C. is in the range of 3,000 to 40,000Pa*s, (d) the composition may have a combination of properties (a) and(b), (e) the composition may have a combination of properties (a) and(c), (f) the composition may have a combination of properties (b) and(c), or (g) the composition may have a combination of properties (a),(b) and (c).

In some embodiments, which may be used in conjunction with the precedingaspects, the composition may further comprise a first physicalcrosslinking agent comprising a plurality of hydrogen bonding groups.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the composition may further comprise animaging agent, such as a radiopaque agent, an MRI contrast agent or anultrasound contrast agent.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the unsaturated groups may be selectedfrom —CH═CH₂ and —C≡CH groups.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first polysiloxane having two or moreunsaturated groups may be a vinyl-terminated polysiloxane, anacrylate-terminated polysiloxane, a methacrylate-terminatedpolysiloxane, or an alkyne-terminated polysiloxane.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first hydride material may havebetween 2 and 20 hydride groups.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the catalyst may be selected from aplatinum catalyst, a rhodium catalyst, a ruthenium catalyst, a palladiumcatalyst, an iridium catalyst, a boron trihydride catalyst, and aphosphine catalyst.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first silanol compound may be ahydroxy-terminated polysiloxane.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first filler may be a silica fillercharacterized by a surface area of 100-500 m²/g.

In some aspects, the present disclosure pertains to a system, whichcomprises two or more composition portions that when combined form ancomposition in accordance with any of the above aspects and embodiments,and the two or more composition portions may include a first compositionportion and a second composition portion.

In some aspects, the present disclosure pertains to a system, whichcomprises (a) an composition in accordance with any of the above aspectsand embodiments and (b) a delivery device containing the composition.The system may be used, for example, for controlling the movement ofbodily fluid within a patient. In some of these embodiments, the systemmay comprise two or more composition portions that when combined formthe composition, and the two or more composition portions may include afirst composition portion and a second composition portion separatedfrom each other within the delivery device.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first composition portion maycomprise the first polysiloxane having two or more unsaturated groups,the first silanol compound, and the first filler, the second compositionportion may comprise the first hydride material having two or morehydride groups, a second silanol compound, and a second filler; thecatalyst may be within at least one of the first and second compositionportions; the first and second silanol compounds may be the same ordifferent; and the first and second fillers may be the same ordifferent.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first and second composition portionsmay each have a viscosity as measured by oscillatory rheology at 0.1 Hzand 1% strain at 25° C. that is at least ten-fold, beneficially at leastone-hundred-fold, more beneficially at least five-hundred-fold, greaterthan a viscosity of the composition as measured by flow rheology at afrequency of 30 Hz at 25° C. In certain of these embodiments, the (a)the first composition portion may further comprise a first physicalcrosslinking agent comprising a plurality of hydrogen bonding groups andthe second composition portion may further comprise a second physicalcrosslinking agent comprising a plurality of hydrogen bonding groups,wherein the first and second physical crosslinking agents may be thesame or different and/or (b) the first composition portion may furthercomprise a first imaging agent and the second composition portion mayfurther comprise a second imaging agent, wherein the first and secondimaging agents may be the same or different.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the delivery device may be configured tomix the first and second composition portions to form the composition inthe delivery device and to deliver the composition into a body of thepatient. In certain of these embodiments, the delivery device maycomprise a first container comprising the first composition portion, asecond container comprising the second composition portion, a mixerconfigured to mix the first and second composition portions, and acatheter.

In certain aspects, the present disclosure pertains to a compositioncomprising a polysiloxane having two or more alkoxy groups, a silanolcompound having two or more silanol groups, and a first filler, in which(a) the composition may have a viscosity as measured by oscillatoryrheology at 0.1 Hz and 1% strain at 25° C. that is at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity of the composition asmeasured by flow rheology at a frequency of 30 Hz at 25° C., (b) thecomposition may cure, when measured at 37° C., within a time period of 1minute to 120 minutes, beneficially 15 minutes to 120 minutes, (c) afterbeing allowed to anneal for a period of 7 days at 70° C., thecomposition may have a viscosity as measured using oscillatory rheologyat a frequency of 0.1 Hz, and a strain of 1% at 25° C. or 37° C. may bein the range of 3,000 to 40,000 Pa*s, (d) the composition may have acombination of properties (a) and (b), (e) the composition may have acombination of properties (a) and (c), (f) the composition may have acombination of properties (b) and (c), or (g) the composition may have acombination of properties (a), (b) and (c).

In some embodiments, which may be used in conjunction with the precedingaspects, the polysiloxane may be a poly(alkoxysiloxane).

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the alkoxy groups of the polysiloxane maybe selected from ethoxy groups.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the silanol compound may be ahydroxy-terminated polysiloxane.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first filler may be a silica fillercharacterized by a surface area of 100-500 m²/g.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the composition may further comprise acatalyst for catalyzing a reaction between the alkoxy groups and thesilanol groups. In some of these embodiments, the catalyst may beselected from a tin-based catalyst and a titanium-based catalyst.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the composition further may comprise adiluent. In some of these embodiments, the diluent may betrialkylsiloxy-terminated polysiloxane.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the composition may further comprise animaging agent.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the composition may further comprise aphysical crosslinking agent comprising a plurality of hydrogen bondinggroups.

In some aspects, the present disclosure pertains to a system, whichcomprises two or more composition portions that when combined form acomposition in accordance with any of the above aspects and embodiments,and the two or more composition portions may include a first compositionportion and a second composition portion.

In some aspects, the present disclosure pertains to a system, whichcomprises (a) a composition in accordance with any of the above aspectsand embodiments and (b) a delivery device containing the composition.The system may be used, for example, for controlling the movement ofbodily fluid within a patient. In some of these embodiments, the systemmay comprise two or more composition portions that when combined formthe composition, and the two or more composition portions may include afirst composition portion and a second composition portion separatedfrom each other within the delivery device.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first composition portion maycomprise the polysiloxane having two or more alkoxy groups, the silanolcompound having two or more silanol groups, and the first filler; andthe second composition portion may comprise a second filler, thecatalyst for catalyzing a reaction between the alkoxy groups and thesilanol groups, and a diluent. In some of these embodiments, (a) thefirst composition portion may further comprise a first imaging agent andthe second composition portion may further comprise a second imagingagent, wherein the first and second imaging agents may be the same ordifferent and/or (b) the first composition portion may further comprisea first physical crosslinking agent comprising a plurality of hydrogenbonding groups and the second composition portion may further comprise asecond physical crosslinking agent comprising a plurality of hydrogenbonding groups, wherein the first and second physical crosslinkingagents may be the same or different.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the first and second composition portionsmay each have a viscosity as measured by oscillatory rheology at 0.1 Hzand 1% strain at 25° C. that is at least ten-fold, beneficially at leastone-hundred-fold, more beneficially at least five-hundred-fold, greaterthan a viscosity of the composition as measured by flow rheology at afrequency of 30 Hz at 25° C.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the delivery device may be configured tomix the first and second composition portions to form the composition inthe delivery device and to deliver the composition into a body of thepatient.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the delivery device may comprise a firstcontainer comprising the first composition portion, a second containercomprising the second composition portion, a mixer configured to mix thefirst and second composition portions, and a catheter.

DETAILED DESCRIPTION

As used herein, a material is described as a “fluid” if it is flowable,as is the case with, for example, liquid, semi-solid, and viscoelasticmaterials.

For the purposes of this disclosure, the terms “crosslinkablecomposition,” “crosslinkable addition-cure composition,” “crosslinkablecondensation-cure composition,” “curable composition,” “curableaddition-cure composition,” and “curable condensation-cure composition,”generally refer to a polymer-based fluid that is capable of beingdelivered to a delivery site, after which crosslinking (i.e., curing) ofthe material continues to progress at the delivery site. For thepurposes of this disclosure, the term “addition-cure” refers to aprocess in which components are crosslinked (i.e., cured) and in whichthere are no byproducts of the crosslinking process. An example of anaddition-cure process is one in which the reactants include one or morecomponents comprising carbon-carbon multiple bonds or carbon-other-atommultiple bonds (e.g., alkene, alkyne, carbonyl, imine, etc.) are reactedand in which there are no byproducts of the reaction. One specificexample of an addition-cure process employed hereinbelow is the reactiona vinyl group with a hydride to produce an ethylene bridge. For thepurposes of this disclosure, the term “condensation-cure” refers to aprocess in which components are crosslinked (i.e., cured) and in whichwater, alcohol or acid is a byproduct of the crosslinking process. Anexample of a condensation-cure process is one in which one or morecomponents comprising silanol groups are reacted one or more componentscomprising alkoxy groups and in which alcohol is a byproduct of thereaction as described hereinbelow.

Although the detailed description of the present disclosure sets forthaddition-cure compositions, systems and methods as well ascomposition-cure compositions, systems and methods, it should beunderstood that various aspects of the present disclosure are not solimited.

In various aspects, compositions in accordance with the presentdisclosure are delivered into a body of a patient as discussed in moredetail below. For example, the compositions may be dispensed onto anytissue or into any body cavity or body lumen of a patient, including,for example, a fallopian tube, a ureter, or the vasculature of apatient). For example, the compositions may be used in a number ofapplications including vascular embolization, treatment of arteriovenousmalformation, treatment of AV fistulas, treatment of abdominal aorticaneurysms, intracranial aneurysms or pulmonary aneurysm, space fillingand bulking in a variety of tissues, prevention of tissue adhesion,hernia repair, treatment of reflux, temporary or permanent occlusion ofbody lumens for a variety of applications including sterilization andprevention of calculus migration during lithotripsy, and treatment ofhemorrhage.

In various aspects, the compositions described herein are injected ordeposited into a delivery site in a body of a patient through the use ofa delivery system. In various embodiments, the delivery system maycomprise a catheter. As used herein, a “catheter” is any device that maybe introduced into or adjacent to a patient's body or target locationwithin a patient's body, and comprises at least one lumen of anyappropriate size, shape or configuration for the movement of fluidtherethrough. As used herein, compositions described as being“injected”, “deposited”, “delivered” and the like include compositionsthat are placed via a delivery system at a delivery location on orwithin a patient's body using any suitable means, includingsyringe-based injection. Depending on fluid viscosity, a hand-poweredsyringe-assist, pneumatic or mechanical pressure pump, or other devicemay be used to control the flow rate and/or improve ease/force ofinjection.

The compositions of the present disclosure typically include one or morepolysiloxane-based polymers (i.e., polymers having repeating —Si—O—bonds in the polymer backbone). Polysiloxane-based polymers for use inthe present disclosure include those comprising homopolymer and/orcopolymer regions consisting of, or containing, one or moreorgano-siloxane monomers, including dialkylsiloxane monomers,diarylsiloxane monomers and/or alkylarylsiloxane monomers, such asdimethylsiloxane, diethylsiloxane, methylethylsiloxane,methylphenylsiloxane and/or diphenylsiloxane monomers, to name a fewexamples. In various beneficial embodiments described herein,polydialkylsiloxane-based polymers, including polydimethylsiloxane(PDMS)-based polymers, are employed. PDMS-based polymers are beneficialfor use in the present disclosure for a variety of reasons, includinglow relative viscosity at higher molecular weights (MW), theirwell-established use in medical devices, and their inherentbiocompatibility. While polysiloxane-based polymers are exemplified, itis to be understood that other biostable, elastomeric polymers may beemployed in place of or in addition to the polysiloxane-based polymersdescribed herein, including natural rubbers, synthetic rubbers such aspolydienes, polyolefins such as polyisobutylene, polyurethanes,polyureas, polyalkylene oxides such as polyethylene oxide (PEO) andpolypropylene oxide (PPO), as well as copolymers, including blockcopolymers, of two or more of the foregoing.

As used herein, a “silanol” or “silanol compound” is a compound thatcomprises one or more silanol (Si—OH) groups and is commonly apolysiloxane-based polymer that comprises two or more silanol groups,for example a hydroxy-terminated PDMS, among other examples.

In some aspects, compositions in accordance with the present disclosure(also referred to herein as “addition-cure compositions”) comprise ahydride material having two or more hydride groups and a polysiloxanehaving two or more unsaturated groups. In various embodiments, theaddition-cure compositions may further comprise a silanol compound, afiller, a catalyst for catalyzing a reaction between the hydride groupsof the hydride material and the unsaturated groups of the polysiloxane,or a combination of any two or all three of the foregoing additionalcomponents. In certain embodiments, the addition-cure compositions maycomprise further additional components, including, for example, a firstphysical crosslinking agent comprising a plurality of hydrogen bondinggroups, an imaging agent, or both.

In certain embodiments, (a) the addition-cure compositions have aviscosity as measured by oscillatory rheology at 0.1 Hz and 1% strain at25° C. that is at least ten-fold, beneficially at leastone-hundred-fold, more beneficially at least five-hundred-fold, greaterthan a viscosity of the composition as measured by flow rheology at afrequency of 30 Hz at 25° C., (b) the addition-cure compositions curewhen measured at 37° C. within a time period of 1 minute to 120 minutes,beneficially 15 minutes to 120 minutes, (c) after being allowed toanneal for a period of 7 days at 70° C., the addition-cure compositionshave a viscosity as measured using oscillatory rheology at a frequencyof 0.1 Hz and a strain of 1% at 25° C. or 37° C. is in the range of3,000 to 40,000 Pa*s, (d) the addition-cure compositions have acombination of properties (a) and (b), (e) the addition-curecompositions have a combination of properties (a) and (c), (f) theaddition-cure compositions have a combination of properties (b) and (c),or (g) the addition-cure compositions have a combination of properties(a), (b) and (c).

Rheological measurements are made using a TA Instruments (Newcastle,Del., USA) Discovery HR-1 rheometer. For property (a), the compositionis placed into a 25 mm parallel plate setup (using sandblasted plates toavoid slip), a Peltier system (TA Instruments) is used to control thattemperature and maintain a gap of 1000 microns, and (i) a firstviscosity is measured using oscillatory rheology at 1% strain and 0.1 Hz(lower shear) at 25° C., (ii) a second viscosity is measured using flowrheology at a frequency of 30 Hz at 25° C. (higher shear), and adetermination is made as to whether the first viscosity value is atleast ten-fold, beneficially at least one-hundred-fold, morebeneficially at least five-hundred-fold greater than the secondviscosity value. For property (b), the composition is loaded onto arheometer with a 25 mm parallel plate setup (see above) and measurementsare taken at constant frequency and strain (f=10 rad/s, γ=1%) over thecourse of 90 minutes to observe the cure time and profile; gel time(time of cure) is defined as the time at which a peak of the phase angle(8) is observed. For property (c), the composition is allowed to annealfor a period of 7 days at 70° C., after which viscosity is measuredusing oscillatory rheology employing the TA Instruments system describedabove at a temperature of 25° C. or 37° C., a frequency of 0.1 Hz and astrain of 1%. Viscosity measured by flow rheology provides an indicationof the properties of the composition under shear conditions similar tothe conditions placed on the composition during delivery from a deliverydevice. Viscosity measured by flow rheology provides an indication ofthe properties of the composition within the body (e.g., in an aneurysm)where shear conditions are experienced having low strain and lowfrequency. Curing time will change based on temperature and curing willtake place in the within the body at 37° C.; a time period of 15 minutesbeing selected in certain embodiment to correspond approximately to thetime required to fill a space (e.g., an aneurysm) within the body, and120 minutes being selected in certain embodiments to allow the materialto cure within a time selected to correspond approximately the of aprocedure.

In various aspects, addition-cure compositions in accordance with thepresent disclosure may be delivered into a body of a patient asdiscussed in more detail below.

In certain embodiments, the addition-cure compositions may contain500-5000 grams of the polysiloxane having two or more unsaturated groupsper mole of the hydride groups. For the purposes of this disclosure,“unsaturated groups” are groups with less than the maximum number ofhydrogen atoms per carbon (not saturated with hydrogen atoms), includinggroups with carbon-carbon double or triple bonds such as alkene oralkyne groups. Specific examples of polysiloxanes having two or moreunsaturated groups include unsaturated-group-terminated polysiloxanessuch as vinyl-terminated PDMS, acrylate-terminated PDMS, ormethacrylate-terminated PDMS).

It is further noted that an excess amount of hydride groups(stoichiometrically) relative to vinyl groups can lead to the productionof gas. Thus, in those embodiments, where gas is not desired, theaddition-cure composition may have a ≥0.9:1 vinyl-group-to-hydride-groupmolar ratio.

In certain embodiments, the weight average molecular weight of all ofthe substituents in the addition-cure compositions, other than thefiller and the imaging agent (if present), ranges from 2,000 to 25,000Da, typically 4,000 to 16,000 Da.

In some embodiments, addition-cure compositions of the presentdisclosure may be provided by combining a first addition-curecomposition portion that comprises a polysiloxane having two or moreunsaturated groups (which may beneficially have a viscosity as measuredby oscillatory rheology as described above that is at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity as measured by flow rheologyrelative as described above) with a second addition-cure compositionportion that comprises a hydride material having two or more hydridegroups (which may beneficially have a viscosity as measured byoscillatory rheology as described above that is at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity as measured by flow rheologyas described above) to form a crosslinkable addition-cure composition(e.g., one suitable for immediate delivery to a subject and preferablyhaving one or more viscosity and/or cure characteristics such as thosedescribed above). A catalyst for catalyzing a reaction between theunsaturated groups of the polysiloxane and the hydride groups of thehydride material may be provided within either one or both of the firstand second addition-cure composition portions. Typically, the catalystis included in the first addition-cure composition portion containingthe polysiloxane having two or more unsaturated groups but not with thesecond addition-cure composition portion containing the hydride materialhaving two or more hydride groups. Typically, the ratio of the volume ofthe first addition-cure composition portion to the volume of the secondaddition-cure composition portion is approximately equal (−1:1),typically ranging, for example, from 2:1 to 1:2, more typically 1.5:1 to1:1.5, among other possible proportions. To enhance mixing, theviscosities of the first and second addition-cure composition portionswill be similar, for example, the oscillatory viscosity of the first andsecond addition-cure composition portions at a frequency of 0.1 Hz at25° C. may be within +/−60% of one another.

In some embodiments, the crosslinkable addition-cure compositions may beprovided by combining (a) a first addition-cure composition portion thatcomprises a first polysiloxane having two or more unsaturated groups, afirst silanol compound, and a first filler with (b) a secondaddition-cure composition portion that comprises a hydride materialhaving two or more hydride groups, a second silanol compound (which maybe the same as or different from the first silanol compound), and asecond filler (which may be the same as or different from the firstfiller). In various embodiments, a catalyst for catalyzing a reactionbetween the unsaturated groups of the polysiloxane and the hydridegroups of the hydride material is provided within either one or both ofthe first and second addition-cure composition portions.

In various embodiments, a physical crosslinking agent comprising aplurality of hydrogen bonding groups (e.g., —OH groups, —NH groups,etc.) may be provided within either one or both of the first and secondaddition-cure composition portions. In embodiments where a firstphysical crosslinking agent is provided within the first addition-curecomposition portion and a second physical crosslinking agent is providedwithin the second addition-cure composition portion, the first andsecond physical crosslinking agents may be the same or different.

In various embodiments, an imaging agent may be provided within eitherone or both of the first and second addition-cure composition portions.In embodiments where a first imaging agent is provided within the firstaddition-cure composition portion and a second imaging agent is providedwithin the second addition-cure composition portion, the first andsecond imaging agents may be the same or different.

In some embodiments, the unsaturated groups of the polysiloxane havingtwo or more unsaturated groups may be selected from —CH═CH₂ and —C≡CHgroups. In some embodiments, the polysiloxane having two or moreunsaturated groups has a weight average molecular weight that rangesfrom 4,000 to 20,000 Da.

In some embodiments, the polysiloxane having two or more unsaturatedgroups is a vinyl-terminated polysiloxane, an acrylate-terminatedpolysiloxane, a methacrylate-terminated polysiloxane, or analkyne-terminated polysiloxane.

Vinyl-terminated PDMS, e.g.,

where n is an integer, is available, for instance, as DMS-V22 fromGelest, Inc., Morrisville, Pa., USA or GP-977 from Genesee PolymersCorporation, Burton, Mich., USA.

For purposes of the present disclosure a “hydride group” is a reactivegroup in which hydrogen is bonded to another atom. Examples of hydridematerial having two or more hydride groups include both small moleculehydrides and polymeric hydrides including multifunctional PDMS hydride,for example,

where n and m are integers, such as HMS-082 or HMS-151 from Gelest, Inc.and GP-236 from Genesee Polymers Corporation. In certain embodiments,hydride materials are employed which contain from 2 to 20 hydride groupsper molecule, typically from 3 to 10 hydride groups per molecule, moretypically from 5-6 hydride groups per molecule. While silicon hydride(Si—H) groups are exemplified throughout the present disclosure, it isto be understood that other hydride groups, in particular, carbonhydride (C—H) groups, may be used in place of the various siliconhydride groups that are described herein. For example, a hydridematerial comprising two or more methyl groups may react with apolysiloxane having two or more unsaturated groups via a peroxideinitiator in some embodiments.

The use of such hydride materials can result in relatively fast reactionkinetics (e.g. with cure occurring in less than 5 minutes). To theextent that it may be desirable to retard the reaction rate to someextent (for example, in the case of AAA treatment, a cure time of 15-120minutes may be desirable), crosslinking reaction kinetics may be slowedby the addition of a polyvinylated small molecule catalyst modifier suchas 1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane,

available from Gelest, among others.

Examples of hydride material having two or more hydride groups furtherinclude hydride-terminated PDMS, for example,

where n is an integer, such as DMS-H11 and DMS-H21 available fromGelest, Inc. or GP-536 and GP-499 available from Genesee PolymersCorporation. In certain embodiments, a mixture of hydride-terminatedPDMS may be employed, for example, a mixture of hydride material with aweight average molecular weight of 4-10 kDa and a hydride material witha weight average molecular weight of 11-20 kDa may be employed.

In various embodiments, the catalyst for catalyzing a reaction betweenunsaturated groups and hydride groups in the addition-cure compositionsof the present disclosure may be selected from a platinum catalyst, arhodium catalyst, a ruthenium catalyst, a palladium catalyst, an iridiumcatalyst, a boron trihydride catalyst, and a phosphine catalyst.

In various embodiments, silanol compounds for use in the addition-curecompositions of the present disclosure include silanol-terminatedpolymers, such as hydroxy-terminated polysiloxanes, for example,

where n is an integer. Specific examples of such materials includeDMS-S12, DMS-S21 and DMS-S31 available from Gelest, Inc. In certainembodiments, hydroxy-terminated polysiloxanes may be selected which havea weight average molecular weight that is less than 4,000 Daltons.

For purposes of this disclosure, a “filler” is a solid component addedto a composition to impart rheological modification, mechanical propertymodification, or both. Fillers for use in the present disclosure includevarious inorganic fillers, such as carbon fillers (e.g., carbon black),metal oxide fillers (e.g., titanium dioxide, zinc oxide, etc.),carbonate fillers (e.g., calcium carbonate), and silica fillers. Silicafillers, including fumed, precipitated, platelet and passivated silicafillers, are available in a range of sizes and surface areas and areavailable from a variety of vendors, including Sigma Aldrich. In certainembodiments, silica fillers may be characterized by a surface area of100-500 m²/g, among other possible values. As a general rule of thumb,increased viscosity may be achieved by using fillers with higher surfacearea, fillers with smaller particle size (which is related to surfacearea), or both. Fillers for use in the present disclosure may range inaggregate particle size from 0.1 to 1.0 μm, among other values, forexample, ranging from 0.01 to 10.0 μm in aggregate particle size, amongother possibilities.

Typically, the addition of the fillers will improve mechanicalproperties (e.g., tensile strength, compressive strength, elasticmodulus and/or durometer) of the final cured material. In certainembodiments, the fillers are selected to provide the addition-curecompositions of the present disclosure (i.e., the crosslinkableaddition-cure compositions, as well as the first and secondaddition-cure composition portions used to form the same) withshear-thinning or thixotropic fluid properties, for example, to ensurethat the compositions have a viscosity, as measured by oscillatoryrheology at 0.1 Hz and 1% strain at 25° C. that is preferably by atleast ten-fold, beneficially at least one-hundred-fold, morebeneficially at least five-hundred-fold, greater than a viscosity asmeasured by flow rheology at a frequency of 30 Hz at 25° C. Thisproperty is particularly beneficial for delivery through low profiledelivery systems, as the application of pressure (shear) in the deliverysystem lowers the apparent viscosity of the fluids, allowing the fluidsto be more readily injected. Upon the removal of shear (e.g., as thefluid exits the delivery system) the composition returns to a morestructured form, with high apparent viscosity helping to preventmigration of the injected material (e.g. in the case of injection intoan aneurysm sac, preventing non-target embolization while being able tofill the entire aneurysm sac and to flow around any prosthesis, such asa stent graft, in the sac).

Other ways to adjust the rheological characteristics of the compositionsof the present disclosure include adjusting either the surface area ofthe filler or particle size of the filler, with higher surface area andsmaller particles generally expected to increase the interactionsbetween the filler and the surrounding medium, therefore providinghigher viscosity).

It has been found that, in certain embodiments, the inclusion of asilanol compound can enhance the shelf stability of the first and secondaddition-cure composition portions described herein. For example, it hasbeen found that the addition of a silanol compound can counteract adecrease in viscosity over time of a mixture of vinyl-terminated PDMS,hydride PDMS and silica that might otherwise occur in the absence of thesilanol compound. In certain embodiments, a weight ratio of silanolcompound to silica of between 2:1 and 1:2, preferably 1:1, may beuseful. In some embodiments, silanol compounds having a weight averagemolecular weight (MW) ranging, for example, from 100 to 2000, typicallyfrom 200 to 1000, more typically from about 500 to 600 may be employed.

In some embodiments, imaging agents for use in the addition-curecompositions of the present disclosure may be selected, for example,from MRI (magnetic resonance imaging) contrast agents, ultrasoundcontrast agents, and radiopaque agents, including for instance,radiopaque metals, radiopaque metal alloys, radiopaque metal oxides andradiopaque polymers, including iodinated polymers. In particularembodiments, the radiopaque agent may be selected from tantalum,tungsten, bismuth (III) oxide, zinc oxide, titanium dioxide and zinctitanate. Contrast agents for use in conjunction with magnetic resonanceimaging (MRI), include contrast agents that contain elements withrelatively large magnetic moment such as gadolinium, manganese and iron(e.g., Gd(III), Mn(II), Fe(III), etc.) and compounds (includingchelates) containing the same, such as gadolinium ion chelated withdiethylenetriaminepentaacetic acid. Contrast agents for use inconjunction with ultrasound imaging include microbubbles filled withsuitable gases such as air, carbon dioxide, oxygen, nitrogen, sulfurhexafluoride, perfluorobutane or octafluoropropane, among others.

In various embodiments, physical crosslinking agents for use in theaddition-cure compositions of the present disclosure may comprise aplurality of hydroxy (—OH) groups as hydrogen bonding groups. Examplesof physical crosslinking agents include, hydroxy-terminated polymers anddendrimers such as hydroxy-terminated polysiloxanes (e.g., carbinol(hydroxy) terminated polydimethylsiloxane), hydroxy-terminatedpoly(alkylene oxides) including hydroxy-terminated polyethylene oxideand hydroxy-terminated polypropylene oxide, and hydroxy-terminatedpolyvinyl alcohol. Such hydroxy-terminated polymers may be, for example,linear, or may be multiarmed or dendritic, for example, having three,four, five, six or more arms, one specific example of which is athree-arm polymer of the formula,

where n is an integer. Other examples include sugars, such as sucrose,cellulose, glucose, and dextrose, and potassium phthalate, polyols(e.g., glycerol, diglycerol, triglycerol, tetraglycerol, pentaglycerol,hexaglycerol, ethylene glycol, propylene glycol, butylene glycol,1,5-pentane diol, 1,6-hexane diol, trimethylolpropane, 1,2,6-hexanetriol, pentaerythritol, sorbitol, mannitol, hydroxypropylmethylcelluloseor hydroxypropylethylcellulose) and acrylates (e.g. poly (acrylic acid),2-hydroxyethylmethacrylate, poly (methyl methacrylate-co-ethylacrylate)). Such physical crosslinkers may be provided, for example, ina concentration ranging from 0.5 to 5 wt %, typically 1.0 to 4.0 wt %,more typically about 1.25-3.5 wt %, among other possible amounts.

In certain embodiments, the physical crosslinking agents may be selectedto increase the resting viscosity (i.e., the zero-shear viscosity) ofthe addition-cure compositions of the present disclosure (i.e., thecrosslinkable addition-cure compositions, as well as the first andsecond addition-cure composition portions used to form the same),without significantly impacting the shear-thinning characteristics ofthe material.

In this regard, as noted above, the addition of a silanol compound canbe useful in providing enhanced stability in some embodiments. Theaddition of a silanol compound, however, can act to decrease the restingviscosity of the addition-cure compositions described herein. Whileviscosity may be increased by providing additional filler, this can makedelivery more difficult. However, by providing physical crosslinkingagents such as those described hereinabove, resting viscosity can beincreased, without significantly impacting the shear-thinningcharacteristics of the material. Without being bound by theory, it ishypothesized that such molecules can provide additional hydrogen bondingby bridging between silica particles and/or PDMS chains.

In certain embodiments, it has been found that the average molecularweight of the first and second addition-cure composition portions can beadjusted to enhance the cohesiveness (the ability of the first andsecond addition-cure composition portions to remain attached to a largerbulk rather than breaking into small pieces) under shear. In theseembodiments, the overall molecular weight of the first and secondaddition-cure composition portions (i.e., the weight average molecularweight of all of the substituents in the addition-cure compositions,other than filler and imaging agent, if present) may be less than 12,000Da, for example ranging from 4,000 to 10,000 Da.

In various additional aspects, compositions in accordance with thepresent disclosure (also referred to herein as “condensation-curecompositions”) may comprise a polysiloxane having two or more alkoxygroups, a silanol compound having two or more silanol groups, and anoptional filler. In certain embodiments, the condensation-curecompositions may further comprise additional components, including, forexample, a catalyst for catalyzing a reaction between the alkoxy groupsand the silanol groups, a diluent, a physical crosslinking agentcomprising a plurality of hydrogen bonding groups, an imaging agent, ora combination of any two, any three or all four of the foregoingadditional components.

In certain embodiments, (a) the condensation-cure compositions of thepresent disclosure may have a viscosity as measured by oscillatoryrheology at 0.1 Hz and 1% strain at 25° C. that is at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity as measured by flow rheologyat a frequency of 30 Hz at 25° C., (b) the condensation-curecompositions may cure when measured at 37° C. within a time period of 1minute to 120 minutes, beneficially 15 minutes to 120 minutes, (c) afterbeing allowed to anneal for a period of 7 days at 70° C., thecondensation-cure compositions may have a viscosity as measured usingoscillatory rheology at a frequency of 0.1 Hz and a strain of 1% at 25°C. or 37° C., is in the range of 3,000 to 40,000 Pa*s, (d) thecondensation-cure compositions have a combination of properties (a) and(b), (e) the condensation-cure compositions have a combination ofproperties (a) and (c), (f) the condensation-cure compositions have acombination of properties (b) and (c), or (g) the condensation-curecompositions have a combination of properties (a), (b) and (c).

In some embodiments, condensation-cure compositions in accordance withthe present disclosure may be delivered into a body of a patient asdiscussed in more detail below.

In various embodiments, compositions in accordance with the presentdisclosure may be provided by combining a first condensation-curecomposition portion (which may beneficially have a viscosity as measuredby oscillatory rheology as described above that is at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity as measured by flow rheologyas described above) with a second condensation-cure composition portion(which may beneficially have a viscosity as measured by oscillatoryviscosity as described above that is at least ten-fold, beneficially atleast one-hundred-fold, more beneficially at least five-hundred-fold,greater than a viscosity as measured by flow rheology as describedabove) to form a crosslinkable condensation-cure composition (e.g., onesuitable for immediate delivery to a subject and preferably having oneor more viscosity and/or cure characteristics such as those describedabove). In some of these embodiments, the crosslinkablecondensation-cure compositions may be provided by combining (a) a firstcondensation-cure composition portion that comprises a firstpolysiloxane having two or more alkoxy groups, a first silanol compoundhaving two or more silanol groups, and a first filler with (b) a secondcondensation-cure composition portion that comprises a catalyst forcatalyzing a reaction between the alkoxy groups and the silanol groups,a second filler (which may be the same as or different from the firstfiller) and a diluent.

In certain embodiments, a physical crosslinking agent comprising aplurality of hydrogen bonding groups (e.g., —OH groups, —NH groups,etc.) may be provided within either one or both of the first and secondcondensation-cure composition portions that are combined to form of thecrosslinkable condensation-cure compositions of the present disclosure.In embodiments where a first physical crosslinking agent is providedwithin the first condensation-cure composition portion and a secondphysical crosslinking agent is provided within the secondcondensation-cure composition portion, the first and second catalystsphysical crosslinking agents may be the same or different.

In various embodiments, an imaging agent may be provided within eitherone or both of the first and second condensation-cure compositionportions that are combined to form of the crosslinkablecondensation-cure compositions of the present disclosure. In embodimentswhere a first imaging agent is provided within the firstcondensation-cure composition portion and a second imaging agent isprovided within the second condensation-cure composition portion, thefirst and second imaging agents may be the same or different.

In some embodiments, the alkoxy groups of the polysiloxane having two ormore alkoxy groups may be selected from C1-C5 alkoxy groups (methoxy,ethoxy, propoxy, butoxy, pentoxy, etc.). In some embodiments, the alkoxygroups of the polysiloxane having two or more alkoxy groups may beterminal alkoxy groups, pendant alkoxy groups (i.e., side groups), or acombination of both types of groups.

In some embodiments, the polysiloxane having two or more alkoxy groupscontains pendant alkoxy groups and is a poly(dialkoxysiloxane), such asa poly(diethoxysiloxane) of the formula,

where n is an integer, for example, PSI-021 available from Gelest.

In various embodiments, the catalyst for catalyzing a reaction betweenthe alkoxy groups and the silanol groups within the condensation-curecompositions of the present disclosure may be selected from ametal-based catalyst, such as a tin-, zinc- or titanium-based catalyst(e.g., Tin (II) ethylhexanoate or Titanium (IV) isopropoxide(Ti(OiPr)₄), or an acid or base catalyst.

In various embodiments, silanol compounds for use in conjunction withcondensation-cure compositions of the present disclosure includesilanol-terminated polymers, such as hydroxy-terminated polysiloxanes,for example,

where n is an integer. Specific examples of such materials includeDMS-S12, DMS-S21 and DMS-S31 available from Gelest, Inc. In certainembodiments, hydroxy-terminated polysiloxanes may be selected which havea weight average molecular weight that is between 500 and 30,000Daltons.

In various embodiments, the diluent for use in conjunction withcondensation-cure compositions of the present disclosure may be arelatively inert liquid, for example, a polysiloxane-based diluent, suchas a trialkylsiloxy-terminated polysiloxane, for instance, atrimethylsiloxy-terminated PDMS. Other diluents include other non-polarsolvents or oils.

In various embodiments, fillers for use in conjunction with thecondensation-cure compositions of the present disclosure can be selectedfrom various inorganic fillers, such as carbon fillers (e.g., carbonblack), metal oxide fillers (e.g., titanium dioxide, zinc oxide, etc.),carbonate fillers (e.g., calcium carbonate), and silica fillers. Silicafillers, including fumed, precipitated, platelet and passivated silicafillers, are available in a range of sizes and surface areas and areavailable from a variety of vendors, including Sigma Aldrich. In certainembodiments, silica fillers may be characterized by a surface area of100-500 m²/& among other possible values. Fillers for use in the presentdisclosure may range in aggregate particle size from 0.1 to 1.0 μm,among other values, for example, ranging from 0.01 to 10.0 μm inaggregate particle size, among other possibilities.

As noted above, the addition of the fillers will typically improvemechanical properties (e.g., tensile strength, compressive strength,elastic modulus and/or durometer) of the final cured material and, incertain embodiments, the fillers are selected to provide thecondensation-cure compositions (i.e., the final condensation-curecompositions, as well as the first and second condensation-curecomposition portions used to form the same) with shear-thinning orthixotropic fluid properties, for example, to ensure that thecompositions have a viscosity as measured by oscillatory rheology at 0.1Hz and 1% strain at 25° C. that is preferably by at least ten-fold,beneficially at least one-hundred-fold, more beneficially at leastfive-hundred-fold, greater than a viscosity as measured by flow rheologyat a frequency of 30 Hz at 25° C.

In various embodiments, imaging agents for use in conjunction with thecondensation-cure compositions of the present disclosure can be selectedfrom those described above for use in conjunction with the addition-curecompositions and include MRI contrast agents, ultrasound contrastagents, and radiopaque agents, such as radiopaque metals, radiopaquemetal alloys, radiopaque metal oxides and radiopaque polymers, includingiodinated polymers. In particular embodiments, the radiopaque agent maybe selected from tantalum, tungsten, bismuth (III) oxide, zinc oxide,titanium dioxide and zinc titanate.

In some embodiments, physical crosslinking agents may be used inconjunction with the condensation-cure compositions of the presentdisclosure, can be selected from those described above for use inconjunction with the addition-cure compositions, and may comprise aplurality of hydroxy (—OH) groups as hydrogen bonding groups. Examplesof physical crosslinking agents include, hydroxy-terminated polymers anddendrimers such as hydroxy-terminated polysiloxanes (e.g., carbinol(hydroxy) terminated polydimethylsiloxane), hydroxy-terminatedpoly(alkylene oxides) including hydroxy-terminated polyethylene oxideand hydroxy-terminated polypropylene oxide, and hydroxy-terminatedpolyvinyl alcohol. Such hydroxy-terminated polymers may be, for example,linear, or may be multiarmed or dendritic, for example, having three,four, five, six or more arms, one specific example of which is athree-arm polymer of the formula,

where n is an integer. Other examples include sugars, such as sucrose,cellulose, glucose, and dextrose, and potassium phthalate, polyols(e.g., glycerol, diglycerol, triglycerol, tetraglycerol, pentaglycerol,hexaglycerol, ethylene glycol, propylene glycol, butylene glycol,1,5-pentane diol, 1,6-hexane diol, trimethylolpropane, 1,2,6-hexanetriol, pentaerythritol, sorbitol, mannitol, hydroxypropylmethylcelluloseor hydroxypropylethylcellulose) and acrylates (e.g. poly (acrylic acid),2-hydroxyethylmethacrylate, poly (methyl methacrylate-co-ethylacrylate)). Such physical crosslinkers may be provided, for example, ina concentration ranging from 0.5 to 5 wt %, typically 1.0 to 4.0 wt %,more typically about 1.25-3.5 wt %, among other possible amounts.

As above, in certain embodiments, the physical crosslinking agents maybe selected to increase the resting viscosity (i.e., the zero-shearviscosity) of the condensation-cure compositions (i.e., the finalcondensation-cure compositions, as well as the first and secondcondensation-cure composition portions used to form the same), withoutsignificantly impacting the shear-thinning characteristics of thematerial. In this regard, as noted above, the addition of a silanolcompound may act to decrease the resting viscosity of thecondensation-cure compositions described herein. By providing physicalcrosslinking agents such as those described hereinabove, restingviscosity may be increased, without significantly impacting theshear-thinning characteristics of the material.

In various aspects, systems are provided in which compositions,including the addition-cure compositions and condensation-curecompositions described herein, are delivered from a delivery device to asite on or within a patient.

In some embodiments, the systems may comprise a first compositionportion (e.g., a first addition-cure composition portion or a firstcondensation-cure composition portion) and a second composition portion(e.g., a second addition-cure composition portion or a secondcondensation-cure composition portion) as described hereinabove, whichremain separated from each other within the delivery device until thetime of delivery.

In some embodiments, the delivery device is configured to mix the firstand second composition portions to form an addition-cure orcondensation-cure composition in the delivery device and then deliverthe addition-cure or condensation-cure composition to a site on orwithin a patient.

For example, the delivery device may comprise a first containercomprising a first composition portion, a second container comprising asecond composition portion, a mixer and a delivery catheter. The mixermay be, for example, a passive mixer or a dynamic mixer. In certainembodiments, the distal end of the catheter may be sized to fit within afemoral artery, a lumbar artery, or an inferior mesenteric artery, amongother locations, including other vascular and non-vascular locationssuch as those listed above, among many others.

In certain embodiments, the catheter may have a proximal end and adistal end and may comprise a lumen having a proximal end and a distalend. The mixer may be (a) attached to or incorporated into the proximalend of the catheter or (b) configured to be in line with the proximalend of the catheter. In these embodiments, the mixer may, for example,comprise a first port configured for fluid communication with the firstcomposition portion in the first container, a second port configured forfluid communication with the second composition portion in the secondcontainer, and a third port configured for fluid communication with theproximal end of the lumen of the catheter.

In certain embodiments, the catheter may comprise a first lumen having aproximal end and a distal end and a second lumen having a proximal endand a distal end, and the catheter may be configured to receive thefirst composition portion at the proximal end of the first lumen and toreceive the second composition portion at the proximal end of the secondlumen. Furthermore, the mixer may be (a) attached to or incorporatedinto the distal end of the catheter or (b) configured to be attached tothe distal end of the catheter. In these embodiments, the mixer may, forexample, comprise a first port configured for fluid communication withthe distal end of the first lumen of the catheter, a second portconfigured for fluid communication with the distal end of the secondlumen of the catheter, and a third port configured for fluidcommunication with a delivery site within a patient.

The first and second containers containing the first and secondcomposition portions may be, for example, syringes or compliantchambers. In certain embodiments, the delivery system may furtherinclude a multiple-barreled syringe apparatus having at least first andsecond barrels joined together (e.g., by a flange) and containing therespective the first and second composition portions. Parallel plungersjoined together (e.g., by a second flange) can be used to force thefirst and second composition portions from the first and second barrelsto discharge the first and second composition portions at the same rate(or in the case where the first and barrels are of different diameter ata fixed ratio). An example of a barrel of this type is described in USPat. Pub. No. 20070129672A1 for use in epoxy systems.

As noted above, in certain embodiments, addition-cure andcondensation-cure compositions in accordance with the present disclosuremay be delivered into a body of a patient. For example, compositions inaccordance with the present disclosure may be dispensed onto any tissueor into any body cavity or body lumen of a patient, including, forexample, a fallopian tube, a ureter, or the vasculature of a patient,including an abdominal aortic aneurysm, among various other locations.For example, the compositions may be used in a number of applicationsincluding vascular embolization, treatment of arteriovenousmalformation, treatment of AV fistulas, treatment of abdominal aorticaneurysms, intracranial aneurysms or pulmonary aneurysm, space fillingand bulking in a variety of tissues, prevention of tissue adhesion,hernia repair, treatment of reflux, temporary or permanent occlusion ofbody lumens for a variety of applications including sterilization andprevention of calculus migration during lithotripsy, and treatment ofhemorrhage.

In certain embodiments, the system may comprise an endoprosthesis. Forexample, the endoprosthesis may be a stent graft. The endoprosthesis maybe configured to span an abdominal aortic aneurysm in some embodiments.In certain of these embodiments, the endoprosthesis configured to spanthe aneurysm may be delivered into the aneurysm, and the composition maybe delivered between an outer surface of the endoprosthesis and an innerwall of the aneurysm.

Example 1. PDMS Alkoxy-Silanol Formulation with Silica Filler

Formulations were comprised of two phases (A and B as shown in Table 1)to keep the formulation catalyst separate from the reactive (silanol andalkoxy) groups.

TABLE 1 4:1 Mixing Material Ratio Description Part # Manufacturer Mass %Phase A Filler Fumed Silica Sigma Aldrich 4.50% Silanol DMS-S21 Gelest28.65% Silanol DMS-S31 Gelest 50.93% Crosslinker PSI-021 Gelest 15.92%Phase B Filler Fumed Silica Sigma Aldrich 4.50% Diluent DMS-T21 Gelest85.52% Radiopaque Bismuth (III) Alfa Aesar 7.51% Agent Oxide CatalystTin (II) Sigma Aldrich 2.46% ethylhexanoate

Each phase was mixed in an appropriate size speed mix cup using aplanetary mixer (speed mixer) for 60 seconds at 2000 rpm. Information onthe speed mixing implements for formulating individual phases can befound below in Table 2.

TABLE 2 Component Manufacturer Part Number Speed mixing cups FlackTek(Landrum, SC, USA) Various Sizes Planetary mixer FlackTek DAC 600

Example 2. PDMS Vinyl-Hydride with Silica Filler

Formulations were comprised of two phases (A and B as shown in Table 3)to separate the platinum catalyst from the hydride-functionalized PDMS.Each phase was mixed in an appropriate size speed mix cup using aplanetary mixer.

TABLE 3 Mixed 2:1 (A:B) Material by volume Description Part #Manufacturer Mass % Phase A Filler Fumed Silica Sigma Aldrich 4.00%Vinyl DMS-V22 Gelest 80.00% Terminated PDMS Vinyl VDT-131 Gelest 12.45%Crosslinker Radiopaque Bismuth (III) Alfa Aesar 2.50% Agent OxidePlatinum SIP6830.3 Gelest 0.93% Catalyst Vinyl SIT7900.0 Gelest 0.12%Catalyst Modifier Phase B Filler Fumed Silica Sigma Aldrich 4.00%Hydride HMS-151 Gelest 16.00% Crosslinker Hydride DMS-H25 Gelest 80.00%Terminated PDMS

Example 3. PDMS Vinyl-Hydride with Silica Filler

Formulations were comprised of two phases (A and B as shown in Tables 4to 11) to separate the platinum catalyst from the hydride-functionalizedPDMS. Each phase was mixed in an appropriate size speed mix cup using aplanetary mixer.

TABLE 4 Formula VHS65A (mixed 1:1 by volume) Component Product Supplierwt % Phase A Vinyl PDMS GP-977 Genesee Polymers 74.25% Platinum CatalystSIP6830.3 Gelest 1.05% Catalyst Modifier SIT7900.0 Gelest 0.20% FumedSilica Filler S5505 Sigma Aldrich 9.00% Physical Crosslinker 416177Sigma Aldrich 1.50% Bismuth Oxide 46314 Alfa Aesar 5.00% Silanol PDMSDMS-S12 Gelest 9.00% Phase B Hydride Crosslinker CP-6900 GeneseePolymers 10.00% High MW Hydride PDMS GP-536 Genesee Polymers 13.88% LowMW Hydride PDMS GP-499 Genesee Polymers 29.62% Vinyl PDMS GP-977 GeneseePolymers 22.00% Fumed Silica Filler S5505 Sigma Aldrich 9.00% PhysicalCrosslinker 416177 Sigma Aldrich 1.50% Bismuth Oxide 46314 Alfa Aesar5.00% Silanol PDMS DMS-S12 Gelest 9.00%

TABLE 5 Formulation VHS68 (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 75.75% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 8.00% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 8.00% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 16.57% PDMS Low MW Hydride GP-499 Genesee29.23% PDMS Vinyl PDMS GP-977 Genesee 21.20% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 7.50% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler S5505 Sigma Aldrich 7.50%

TABLE 6 Formulation VHS68A (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 74.75% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 8.50% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 8.50% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 16.10% PDMS Low MW Hydride GP-499 Genesee28.40% PDMS Vinyl PDMS GP-977 Genesee 21.50% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 8.00% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 8.00%

TABLE 7 Formulation VHS68B (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 71.75% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 10.00% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 10.00% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 15.19% PDMS Low MW Hydride GP-499 Genesee26.81% PDMS Vinyl PDMS GP-977 Genesee 21.00% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 9.50% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 9.50%

TABLE 8 Formulation VHS68C (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 75.25% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 8.25% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 8.25% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 16.39% PDMS Low MW Hydride GP-499 Genesee28.91% PDMS Vinyl PDMS GP-977 Genesee 21.20% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 7.75% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 7.75%

TABLE 9 Formulation VHS68D (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 70.75% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 10.50% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 10.50% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 15.19% PDMS Low MW Hydride GP-499 Genesee26.81% PDMS Vinyl PDMS GP-977 Genesee 20.00% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 10.00% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 10.00%

TABLE 10 Formulation VHS68E (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 74.25% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 8.75% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 8.75% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 16.02% PDMS Low MW Hydride GP-499 Genesee28.28% PDMS Vinyl PDMS GP-977 Genesee 21.20% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 8.25% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 8.25%

TABLE 11 Formulation VHS68F (mixed 1:1 by volume) Component ProductSupplier Mass % Phase A Vinyl PDMS GP-977 Genesee 71.25% PhysicalCrosslinker Sucrose 1800 g/L N/A 2.00% (aqueous) Silanol PDMS DMS-S12Gelest 10.25% Platinum Catalyst SIP6830.3 Gelest 1.05% Fumed SilicaFiller Fumed Silica Sigma 10.25% Catalyst Modifier SIT7900.0 Gelest,8K-34454 0.20% Bismuth Oxide Bismuth Oxide Alfa, U23D045 5.00% Phase BHigh MW Hydride GP-536 Genesee 15.28% PDMS Low MW Hydride GP-499 Genesee26.97% PDMS Vinyl PDMS GP-977 Genesee 20.25% Physical CrosslinkerTMPEO-1000 Sigma 3.00% Silanol PDMS DMS-S12 Gelest 9.75% HydrideCrosslinker CP-6900 Genesee 10.00% Bismuth Oxide Bismuth Oxide Alfa,U23D045 5.00% Fumed Silica Filler Fumed Silica Sigma 9.75%

For the Phase A and Phase B of each of the formulations of Tables 4-11,viscosity measured by flow rheology at a frequency of 30 Hz at 25° C.(“Flow Viscosity”) and oscillatory rheology at 1% strain and 0.1 Hz at25° C. (“Phase Viscosity (Osc.)”). Also shown is the dispense viscositywhich is measured by oscillatory rheology at 1% strain and 0.1 Hz at 25°C. Further shown is the gel time, which is based on measurements takenat constant frequency and strain (f=10 rad/s, γ=1%) over the course of90 minutes to observe the cure time and profile, wherein gel time isdefined as the time at which a peak of the phase angle (δ) is observed.

TABLE 12 Phase A Viscosities Phase B Viscosities (Pa*s) (Pa*s) PhasePhase Dispense Gel Viscosity Flow Viscosity Flow Viscosity TimeFormulation (Osc.) Viscosity (Osc.) Viscosity (Pa*s) (Min.) VHS65A 2105521 11794 12 13418 21 VHS68 16693 19 15926 20 9053 22 VHS68A 19134 2320074 23 11369 21 VHS68B 17567 18 18129 20 10851 20 VHS68C 15577 1814777 21 8329 23 VHS68D 19195 19 21109 19 15166 23 VHS68E 18487 19 1612022 12440 21 VHS68F 21583 20 25824 24 14682 22

1.-21. (canceled)
 22. A method for in situ forming a crosslinkedcomposition at a delivery site in the body of a patient, the methodcomprising: delivering a first addition-cure composition to the deliverysite, the first addition-cure composition including apolydimethylsiloxane polymer, a catalyst, and a first fumed silica;delivering a second addition-cure composition to the delivery site, thesecond addition-cure composition including a hydridepolydimethylsiloxane polymer, a second fumed silica, and a secondcrosslinker, the first and/or second addition-cure composition includesa tantalum radiopaque agent; and combining at the delivery site thefirst and second addition-cure compositions to form a crosslinkablecomposition that is cured to form the crosslinked composition at thedelivery site.
 23. The method of claim 1, wherein the first and secondaddition-cure compositions include a tantalum radiopaque agent.
 24. Themethod of claim 1, wherein the catalyst is a platinum catalyst.
 25. Themethod of claim 1, wherein the first and second fumed silicas are thesame.
 26. The method of claim 1, wherein the first addition-curecomposition includes a first crosslinker.
 27. The method of claim 1,wherein the polydimethylsiloxane polymer is a vinyl-terminatedpolydimethylsiloxane.
 28. The method of claim 1, wherein the hydridepolydimethylsiloxane polymer has two or more hydride groups.
 29. Amethod for in situ forming a crosslinked composition at a delivery sitein the body of a patient, the method comprising: delivering a firstaddition-cure composition to the delivery site via a multi-barrelsyringe, the first addition-cure composition including apolydimethylsiloxane polymer, a catalyst, and a first fumed silica;delivering a second addition-cure composition to the delivery site viathe multi-barrel syringe, the second addition-cure composition includinga hydride polydimethylsiloxane polymer, a second fumed silica, and asecond crosslinker, the first and/or second addition-cure compositionincludes a tantalum radiopaque agent; and combining at the delivery sitethe first and second addition-cure compositions to form a crosslinkablecomposition that is cured to form the crosslinked composition at thedelivery site.
 30. The method of claim 8, wherein the first and secondaddition-cure compositions include a tantalum radiopaque agent.
 31. Themethod of claim 8, wherein the catalyst is a platinum catalyst.
 32. Themethod of claim 8, wherein the first and second fumed silicas are thesame.
 33. The method of claim 8, wherein the first addition-curecomposition includes a first crosslinker.
 34. The method of claim 8,wherein the polydimethylsiloxane polymer is a vinyl-terminatedpolydimethylsiloxane.
 35. The method of claim 8, wherein the hydridepolydimethylsiloxane polymer has two or more hydride groups.
 36. Aformulation for in situ forming a crosslinked composition at a deliverysite in the body of a patient, the formulation comprising: a firstaddition-cure composition including a polydimethylsiloxane polymer, acatalyst, and a first fumed silica; a second addition-cure compositionincluding a hydride polydimethylsiloxane polymer, a second fumed silica,and cross-linker, the first and/or second addition-cure compositionincludes a tantalum radiopaque agent, when combined, the first andsecond addition-cure compositions configured to form a crosslinkablecomposition curable to form the crosslinked composition at the deliverysite.
 37. The method of claim 15, wherein the first and secondaddition-cure compositions include a tantalum radiopaque agent.
 38. Themethod of claim 15, wherein the catalyst is a platinum catalyst.
 39. Themethod of claim 15, wherein the first and second fumed silicas are thesame.
 40. The method of claim 15, wherein the first addition-curecomposition includes a first crosslinker.
 41. The method of claim 15,wherein the polydimethylsiloxane polymer is a vinyl-terminatedpolydimethylsiloxane.